Numerous acid-stable or free sulfhydryl-containing proteins, such as xcex2IFN, exhibit biological activity in vivo, which renders them useful as medicaments in therapy. Many illnesses or conditions which can be treated with this type of protein, for example, Multiple Sclerosis (MS) which is currently treated with xcex2-IFN, require administration of a constant or sustained level of medicament to provide the most effective prophylactic and/or therapeutic effects. For example, BETASERON(copyright) (Interferon beta-1b) is currently administered for the treatment of MS at a dose of 9 million IU, injected subcutaneously three time a week. As such, administration of biologically active acid-stable or free sulfhydryl-containing proteins requires frequent subcutaneous injections, which result in fluctuating levels of medicament and poor patient compliance.
As an alternative, the use of biodegradable materials, such as polymers, encapsulating the medicament can be employed as a sustained delivery system. The use of biodegradable polymers, for example, in the form of microparticles or microcarriers, can provide a sustained release of medicament, by utilizing the inherent biodegradability of the polymer to control the release of the medicament thereby providing a more consistent, sustained level of medicament and improved patient compliance.
However, these sustained release devices can exhibit high initial bursts of medicament and minimal release thereafter. In addition, due to the high solution concentration of medicament within and localized around these sustained release devices, the medicament can aggregate thereby increasing immunogenicity in vivo and interfering with the desired release profile for the medicament. Further, methods used to form sustained release compositions can result in loss of activity of the medicament due to the instability of the medicament and the degradative effects of the processing steps. In addition, adsorption of the biologically active acid-stable or free sulfhydryl-containing proteins onto the polymer surface can inhibit the release from the sustained release composition.
Therefore, a need exists for a means of administering biologically active acid-stable or free sulfhydryl-containing proteins, for example, xcex2-IFN in a sustained fashion wherein activity and potency of the protein is maintained.
This invention relates to compositions for the sustained release of biologically active acid-stable or free sulfhydryl-containing proteins, and methods of forming and using said compositions, for the sustained release of biologically active acid-stable or free sulfhydryl-containing proteins, in particular, xcex2-IFN. The sustained release compositions of this invention comprise a biocompatible polymer having dispersed therein a stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation, and at least one surfactant. The stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation of the sustained release composition comprises at least one biologically active acid-stable or free sulfhydryl-containing protein, at least one disaccharide and at least one acidic excipient Optionally, the stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation further comprises a water soluble polymer.
The method of the invention, for forming a composition for the sustained release of biologically active acid-stable or free sulfhydryl-containing proteins, includes dissolving a biocompatible polymer in a polymer solvent to form a polymer solution, adding at least one surfactant and the stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation to the polymer solution, and then solidifying the polymer to form a polymer matrix containing the stabilized biologically active acid-stable or free sulfhydryl-containing protein formulation and the surfactant dispersed therein.
The method of using the sustained release composition of the present invention comprises providing a therapeutically effective blood level of biologically active acid-stable or free sulfhydryl-containing protein, in particular, xcex2-IFN in a subject for a sustained period by administering to the subject a dose of the sustained release composition described herein.
The sustained release composition of the invention overcomes the problem of aggregation of the biologically active acid-stable or free sulfhydryl-containing protein, for example, xcex2-IFN which can occur during processing and/or following administration in vivo, when the biologically active protein is not stabilized. Further, loss of activity of the biologically active protein due to instability of the medicament, and chemical interactions between the biologically active protein and other components, which are contained in or used in formulating the sustained release composition, are minimized.
The advantages of the sustained release formulation for biologically active acid-stable or free sulfhydryl-containing proteins, in particular, xcex2-IFN as described herein, include increased patient compliance and acceptance by eliminating the need for repetitive administration, increased therapeutic benefit by eliminating fluctuations in active agent concentration in blood levels by providing a desirable release profile, and a potential lowering of the total amount of biologically active acid-stable or free sulfhydryl-containing protein necessary to provide a therapeutic benefit, by reducing these fluctuations.